Abstract
Inflammation significantly impacts the progression of Huntington's disease (HD) and the mutant HTT protein determines a pro‐inflammatory activation of microglia. Mesenchymal stem/stromal cells (MSC) from the amniotic membrane (hAMSC), and their conditioned medium (CM‐hAMSC), have been shown to possess protective effects in vitro and in vivo in animal models of immune‐based disorders and of traumatic brain injury, which have been shown to be mediated by their immunomodulatory properties.In this study, in the R6/2 mouse model for HD we demonstrate that mice treated with CM‐hAMSC display less severe signs of neurological dysfunction than saline‐treated ones. CM‐hAMSC treatment significantly delayed the development of the hind paw clasping response during tail suspension, reduced deficits in rotarod performance, and decreased locomotor activity in an open field test. The effects of CM‐hAMSC on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal atrophy and the formation of striatal neuronal intranuclear inclusions. In addition, while no significant increase was found in the expression of BDNF levels after CM‐hAMSC treatment, a significant decrease of microglia activation and inducible nitric oxide synthase levels were observed. These results support the concept that CM‐hAMSC could act by modulating inflammatory cells, and more specifically microglia.
Highlights
Huntington's disease (HD) is a fatal, incurable autosomal dominant neurodegenerative disorder caused by instable expansion of Carmela Giampà and Alessandra Alvino contributed .polyglutamine tract within the resulting mutated HTT protein.[1]
When we measured the area of neuronal intranuclear inclusions (NIIs), we found a marked reduction in mutant huntingtin (mHtt) size in R6/2 treated with CM‐hAMSC when compared with saline‐ (P < 0.0001) or CTRL‐treated (P < 0.0001) R6/2 mice, indicating that the treatment with CM‐hAMSC was able to reduce the aggregation of mutant Huntingtin (Figure 4C)
For the first time, we have tested a cell‐free treatment based on CM‐hAMSC in the R6/2 mouse model of HD
Summary
Polyglutamine (polyQ) tract within the resulting mutated HTT protein (mHTT).[1] Huntington's disease pathology is characterized by a massive loss of neurons in the striatal part of the basal ganglia[2] that causes motor and cognitive dysfunction. As a matter of fact, there is substantial evidence that the expression of mutant HTT protein results in a pro‐inflammatory activation of microglia which influences disease onset and progression.[3] inflammatory cytokines have been detected in the striatum of HD patients compared with that of healthy individuals[4] and in the plasma and cerebrospinal fluid of HD patients.[3] pro‐inflammatory (M1) microglia relevant biomarkers have been detected in the brains of HD patients, which indicates that M1 microglia may play a crucial role in the pathogenesis of HD.[5] These findings indicate that central and peripheral inflammation may represent a critical juncture in the progression and amplification of HD pathology that, if understood, could support the development of anti‐inflammatory‐based treatment options
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